RIPLET, and not TRIM25, is required for endogenous RIG‐I‐dependent antiviral responses

Hayman, Thomas J.; Hsu, Alan; Kolesnik, Tatiana B.; Dagley, Laura F.; Willemsen, Joschka; Tate, Michelle D.; Baker, Paul J.; Kershaw, Nadia J.; Kędzierski, Łukasz; Webb, Andrew I.; Wark, Peter; Kedzierska, Katherine; Masters, Seth L.; Belz, Gabrielle T.; Binder, Marco; Hansbro, Philip M.; Nicola, Nicos A.; Nicholson, Sandra E.

doi:10.1111/imcb.12284

Cited by 80 publications

(78 citation statements)

References 56 publications

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“…Several E3 ligases other than TRIM25 promote ubiquitination of RIG-I leading to controversial discussions about their relative importance (64)(65)(66)(67)(68)(69). Among these are several TRIM proteins (TRIM4, 15,40) and Riplet, a close relative of TRIM25, that lost the B-Box domains and parts of the CC (70)(71)(72).…”

Section: Discussionmentioning

confidence: 99%

Mechanistic insights into RNA binding and RNA-regulated RIG-I ubiquitination by TRIM25

Haubrich

Augsten²,

Álvarez³

et al. 2020

Preprint

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TRIM25 is a ubiquitin E3 ligase active in innate immunity and cell fate decisions. Mounting evidence suggests that TRIM25’s E3 ligase activity is regulated by RNAs. However, while mutations affecting RNA-binding have been described, the precise RNA binding site has not been identified nor which domains are involved. Here, we present biophysical evidence for the presence of RNA binding sites on both TRIM25 PRY/SPRY and coiled-coil domains, and map the binding site on the PRY/SPRY with residue resolution. Cooperative RNA-binding of both domains enhances their otherwise transient interaction in solution and increases the E3 ligase activity of TRIM25. Mutational analysis shows that RNA binding affects ubiquitination of RIG-I in mammalian cells. In addition, we present a simple model system for RNA-induced liquid-liquid phase separation of TRIM25 in vitro, resembling previously observed cellular RNA granules, that facilitates the recruitment of RIG-I.

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Section: Discussionmentioning

confidence: 99%

Mechanistic insights into RNA binding and RNA-regulated RIG-I ubiquitination by TRIM25

Haubrich

Augsten²,

Álvarez³

et al. 2020

Preprint

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“…This is followed by ubiquitination at various sites on the 2CARD by Riplet, TRIM25, TRIM4 and MEX3C. This would fit with several recent observations (Cadena et al, ; Hayman et al, ; Shi et al, ) that Riplet is absolutely required for efficient RIG‐I signaling activation, while TRIM25 is not, as well as explaining why there is seemingly redundancy between the other E3 ligases. In particular, recent work by Cadena et al showed that deletion of TRIM25 from HEK293T and MEF cells results in an increase, not a reduction in RIG‐I activation in response to 5′ppp‐RNA.…”

Section: Trim25's Role In Innate Immunitymentioning

confidence: 99%

TRIM25 and its emerging RNA‐binding roles in antiviral defense

2020

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The innate immune system is the body's first line of defense against viruses, with pattern recognition receptors (PRRs) recognizing molecules unique to viruses and triggering the expression of interferons and other anti-viral cytokines, leading to the formation of an anti-viral state. The tripartite motif containing 25 (TRIM25) is an E3 ubiquitin ligase thought to be a key component in the activation of signaling by the PRR retinoic acid-inducible gene I protein (RIG-I). TRIM25 has recently been identified as an RNA-binding protein, raising the question of whether its RNA-binding activity is important for its role in innate immunity. Here, we review TRIM25's mechanisms and pathways in noninfected and infected cells. We also introduce models that explain how

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“…The notion of different E3 ligases playing critical roles in the activation of RIG-I has recently been challenged with some groups identifying Riplet, and not TRIM25, as the required E3 ligase [126][127][128]. The challenge was raised when Riplet -/-, but not TRIM25 -/-, cell lines failed to induce innate immune signalling upon stimulation [126], although these experiments did not address different time points or other stimulation conditions that may trigger RIG-I activation, or the possibility of functional redundancy.…”

Section: Innate Antiviral Signalling Functions Of Trim25: Rig-i-depenmentioning

confidence: 99%

To TRIM or not to TRIM: the balance of host–virus interactions mediated by the ubiquitin system

Hage

Rajsbaum

2019

Journal of General Virology

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The innate immune system responds rapidly to protect against viral infections, but an overactive response can cause harmful damage. To avoid this, the response is tightly regulated by post-translational modifications (PTMs). The ubiquitin system represents a powerful PTM machinery that allows for the reversible linkage of ubiquitin to activate and deactivate a target's function. A precise enzymatic cascade of ubiquitin-activating, conjugating and ligating enzymes facilitates ubiquitination. Viruses have evolved to take advantage of the ubiquitin pathway either by targeting factors to dampen the antiviral response or by hijacking the system to enhance their replication. The tripartite motif (TRIM) family of E3 ubiquitin ligases has garnered attention as a major contributor to innate immunity. Many TRIM family members limit viruses either indirectly as components in innate immune signalling, or directly by targeting viral proteins for degradation. In spite of this, TRIMs and other ubiquitin ligases can be appropriated by viruses and repurposed as valuable tools in viral replication. This duality of function suggests a new frontier of research for TRIMs and raises new challenges for discerning the subtleties of these pro-viral mechanisms. Here, we review current findings regarding the involvement of TRIMs in host-virus interactions. We examine ongoing developments in the field, including novel roles for unanchored ubiquitin in innate immunity, the direct involvement of ubiquitin ligases in promoting viral replication, recent controversies on the role of ubiquitin and TRIM25 in activation of the pattern recognition receptor RIG-I, and we discuss the implications these studies have on future research directions.

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RIPLET, and not TRIM25, is required for endogenous RIG‐I‐dependent antiviral responses

Cited by 80 publications

References 56 publications

Mechanistic insights into RNA binding and RNA-regulated RIG-I ubiquitination by TRIM25

Mechanistic insights into RNA binding and RNA-regulated RIG-I ubiquitination by TRIM25

TRIM25 and its emerging RNA‐binding roles in antiviral defense

To TRIM or not to TRIM: the balance of host–virus interactions mediated by the ubiquitin system

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